Synthesis and PKC binding of a new class of a-ring diversifiable bryostatin analogues utilizing a double asymmetric hydrogenation and cross-coupling strategy.

The design, asymmetric synthesis, and biological evaluation of a new class of bryostatin analogues based on a pseudosymmetric spacer domain are described. An aryl bromide diversification site is incorporated allowing access to systematically varied analogues. The new analogues all exhibit potent, nanomolar affinity to PKC.

[1]  S. Buchwald,et al.  Catalysts for Suzuki-Miyaura coupling processes: scope and studies of the effect of ligand structure. , 2005, Journal of the American Chemical Society.

[2]  Ryoji Noyori,et al.  Asymmetric hydrogenation of .beta.-keto carboxylic esters. A practical, purely chemical access to .beta.-hydroxy esters in high enantiomeric purity , 1987 .

[3]  T. Hashimoto,et al.  Bis(((S)-binaphthoxy)(isopropoxy)titanium) oxide as a mu-oxo-type chiral Lewis acid: application to catalytic asymmetric allylation of aldehydes. , 2003, Journal of the American Chemical Society.

[4]  P. Blumberg,et al.  Highly lipophilic phorbol esters as inhibitors of specific [3H]phorbol 12,13-dibutyrate binding. , 1985, Cancer research.

[5]  G. Schwartz,et al.  Bryostatin-1: A Novel PKC Inhibitor in Clinical Development , 2003, Cancer investigation.

[6]  B. Bienfait,et al.  The Lipophilicity of Phorbol Esters as a Critical Factor in Determining the Pattern of Translocation of Protein Kinase C δ Fused to Green Fluorescent Protein* , 2000, The Journal of Biological Chemistry.

[7]  M. Wills,et al.  Chemistry and clinical biology of the bryostatins. , 2000, Bioorganic & medicinal chemistry.

[8]  John P. Wolfe,et al.  A Highly Active Catalyst for Palladium-Catalyzed Cross-Coupling Reactions: Room-Temperature Suzuki Couplings and Amination of Unactivated Aryl Chlorides , 1998 .

[9]  R. Mohammad,et al.  The addition of bryostatin 1 to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy improves response in a CHOP-resistant human diffuse large cell lymphoma xenograft model. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  T. Meyer,et al.  Function oriented synthesis: the design, synthesis, PKC binding and translocation activity of a new bryostatin analog. , 2004, Current drug discovery technologies.

[11]  D. Alkon,et al.  Dual effects of bryostatin-1 on spatial memory and depression. , 2005, European journal of pharmacology.

[12]  C. Holmquist,et al.  The conversion of olefins to β-keto esters: Ozonolysis of olefins followed by in situ reduction with tin(II) chloride in the presence of ethyl diazoacetate. , 1990 .

[13]  N. Lindquist,et al.  Potent cytotoxins produced by a microbial symbiont protect host larvae from predation , 2004, Oecologia.

[14]  D. Alkon,et al.  Therapeutic effects of PKC activators in Alzheimer's disease transgenic mice. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Mark Frigerio,et al.  The chemistry and biology of the bryostatin antitumour macrolides. , 2002, Natural product reports.

[16]  S. Hannick,et al.  An improved procedure for the Blaise reaction: a short, practical route to the key intermediates of the saxitoxin synthesis , 1983 .

[17]  Paul A Wender,et al.  Role of the A-ring of bryostatin analogues in PKC binding: synthesis and initial biological evaluation of new A-ring-modified bryologs. , 2005, Organic letters.

[18]  Gang Zhao,et al.  One-pot preparation of β-hydroxy esters catalysed by a bis(cyclopentadienyl)titanium(IV) dichloride–zinc system , 1992 .

[19]  Christopher S. Poss,et al.  Two-directional chain synthesis : an application to the synthesis of (+)-mycoticin A , 1993 .

[20]  Blaise Lippa,et al.  The practical synthesis of a novel and highly potent analogue of bryostatin. , 2002 .

[21]  Shadan Ali,et al.  Sensitization of human breast cancer cells to gemcitabine by the protein kinase C modulator bryostatin 1 , 2003, Cancer Chemotherapy and Pharmacology.

[22]  T. Katsuki,et al.  A rapid esterification by means of mixed anhydride and its application to large-ring lactonization. , 1979 .